The skin is a constantly renewing organ which undergoes a series of regulated changes as the cells of the basal layer proliferate and differentiate into the anucleate stratum corneum. In hyperproliferative skin diseases such as psoriasis failure of regulatory processes results in hyperproliferation, inflammation and abnormal keratinization. There is evidence that calcium can regulate the proliferation of keratinocytes in-vitro, and that in other cell systems it is capable of regulating the production of the pro-inflammatory arachidonic acid metabolites. We propose to study the role of calcium and its binding protein, calmodulin, in the epidermis. We will begin by focusing on the relationship between calcium and the arachidonic acid metabolites. We will use in-vitro tissue culture of keratinocytes and HPLC techniques to determine the relationship between the millimolar amounts of calcium available to keratinocytes and the amount and types of arachidonic acid metabolites they produce. We will also examine the ability of the arachidonic acid metabolites to produce calcium fluxes in keratinocytes using 45calcium. If fluxes are noted we will use the calcium blockers including nifedipine, trifluoperazine, anti-calmodulin and the metabolic inhibitor puromycin to determine their source: internal versus external. In addition we will use these same calcium blockers to determine whether the hyperproliferative effect of one of the arachidonic acid metabolites, leukotriene B4, on keratinocytes is mediated via calcium. Finally we will study epidermal phospholipase A2, the rate limiting enzyme of arachidonic acid metabolism. We will compare the activity of phospholipase A2 in normal human epidermis, epidermis from psoriatic plaque and psoriatic uninvolved skin as well as from the epidermis of psoriatics in complete remission. The involvement of calmoculin in the regulation of epidermal phospholipase A2 will be studied. By a systematic investigation into the interaction of calcium and the arachidonic acid metabolites in the skin we will elucidate the role of calcium in the epidermis. This knowledge can then be applied to disease states such as psoriasis where hyperproliferation and inflammation are both a feature.